Over the past several decades, continuous strides have been made to improve the treatment of diabetes mellitus. Approximately 90% of people with diabetes have type 2 diabetes also known as non-insulin dependent diabetes mellitus (NIDDM). Type 2 diabetics generally still make insulin, but the insulin cannot be used effectively by the body's cells. This is primarily because the amount of insulin produced in response to rising blood sugar levels is not sufficient to allow cells to efficiently take up glucose and thus, reduce blood sugar levels.
Often, individuals with NIDDM can initially control their blood glucose levels by taking oral medications. However, oral medications do not slow the progressive loss of β cell function that occurs in type 2 patients and eventually these types of medications are not sufficient to control blood glucose levels.
A large body of pre-clinical and clinical research data suggests that glucagon-like pepide-1 (GLP-1) shows great promise as a treatment for NIDDM especially when oral agents begin to fail. GLP-1 induces numerous biological effects such as stimulating insulin secretion, inhibiting glucagon secretion, inhibiting gastric emptying, enhancing glucose utilization, and inducing weight loss. Further, pre-clinical studies suggest that GLP-1 may also act to prevent the β cell deterioration that occurs as the disease progresses. Perhaps the most salient characteristic of GLP-1 is its ability to stimulate insulin secretion without the associated risk of hypoglycemia that is seen when using insulin therapy or some types of oral therapies that act by increasing insulin expression.
As NIDDM progresses it becomes extremely important to achieve near normal glycemic control and thereby minimize the complications associated with prolonged hyperglycemia. GLP-1 would appear to be the drug of choice. However, the usefulness of therapy involving GLP-1 peptides has been limited by the fact that GLP-1(1–37) is poorly active, and the two naturally occurring truncated peptides, GLP-1(7–37)OH and GLP-1(7–36)NH2, are rapidly cleared in vivo and have extremely short in vivo half-lives. Further, current GLP-1 peptide formulations cannot be given orally and like insulin must be injected. Thus, despite the clear medical advantages associated with therapy involving GLP-1, the short half-life which results in a drug that must be injected numerous times a day has impeded commercial development efforts.
Generally, moving patients to an injectable therapy is quite difficult. Many diabetics are unwilling to undertake any type of intensive injection therapy due to the discomfort associated with the many injections required to maintain adequate glucose control. Furthermore, diabetics on insulin are generally required to monitor their blood glucose which involves additional needle sticks. This type of therapy can be both physchologically and physically painful. This is especially true when patients have been treated solely with oral medications throughout the progression of the disease.
Thus, not only is there a need to develop GLP-1 formulations that provide a protracted action when injected such that the number of injections is reduced and glucose monitoring is eliminated, but also GLP-1 formulations that can be delivered by alternative means such as by the pulmonary route and provide a sustained pharmacokinetic profile.
It has been known for a number of years that some proteins can be absorbed through the lung; however, despite this showing, pulmonary delivery has not received wide acceptance as a means for delivering therapeutic peptides. This is due to dramatic decreases in bioavailability that can occur when a peptide is delivered as well as extreme variability in amounts of a particular peptide absorbed even when comparing identical doses given at different times. Efficient pulmonary delivery of a peptide is dependent on the ability to deliver the peptide to the deep lung alveolar epithelium. The extent to which peptides are eliminated before reaching the deep lung depends on characteristics such as size and aerodynamic properties of particles containing the peptide.
By complexing GLP-1 molecules with a basic polypeptide such as protamine and incorporating these complexes into unique particles, the present invention solves the problems associated with the rapid clearance and short half-life of GLP-1 compounds as well as the inefficiency and reduced bioavailability that can occur when peptides are delivered through the pulmonary route. Furthermore, the GLP-1 particles of the present invention have sustained release properties when delivered pulmonarily.
It is known in the art that native GLP-1(7–37)OH can be precipitated with protamine. EP 619322 describes aqueous suspensions of native GLP-1 and protamine which the inventors suggest have a protracted action when administered subcutaneously. In addition, Pridal, et al. discusses protamine-GLP-1 crystals and state that the protracted action of these crystals is due to their slow absorption rate from the subcutaneous injection site. Pridal, et al. (1996) Intln. J. Pharm. 136:53–59. However, the authors use a ratio of GLP-1 to protamine such that the resulting crystals are of a size not particularly suited for efficient pulmonary delivery. Kim et al. also discusses precipitation of native GLP-1 and protamine. Kim, et al. (1995) Pharm. Res. 12:1284–1288. That paper focuses solely on determining the isophane ratio of native GLP-1 to protamine in the presence of various excipients.
This GLP-1 protamine art, however, does not describe the unique particles and compositions encompassed by the present invention. These particles and compositions have properties such as size, solubility characteristics, morphology, and mass mean aerodynamic diameters as well as other aerodynamic properties that distinguish them from the prior art precipitated mixtures. Furthermore, none of the prior art references disclose or suggest the dry powder formulations of the present invention which comprise a mixture of unique particles containing GLP-1, GLP-1 analogs, or GLP-1 derivatives complexed with a basic polypeptide such as protamine. These particles are sufficiently small and possess aerodynamic properties such that they reach the deep lung thereby reducing problems associated with bioavailability and absorption variability. Most importantly, the particles of the present invention and formulations thereof have a sustained pharmacokinetic profile when delivered pulmonarily.